studydm5migu4zj3pb.cloudfront.net/manuscripts/100000/... · study of the blood in chronic...

STUDYOF THE BLOODIN CHRONICRESPIRATORYDIS-EASES, WITH SPECIAL REFERENCETO THE

VOLUMEOF THE BLOOD1

By NOLANL. KALTREIDER, ALBERTOHURTADOANDWILLIAM D. W. BROOKS2

(From the Department of Medicine of the School of Medicine and Dentistry of theUniversity of Rochester and the Medical Clinic of the Strong Memorial and

Rochester Municipal Hospitals, Rochester, New York)

(Received for publication August 6, 1934)

The character of the changes in the blood in cases of chronic pulmonarydiseases has not been settled. Although patients with respiratory dis-turbances often have the appearance of those with polycythemia, it isquestionable whether there is an actual increase in the blood and cellvolume. Some investigators believe that the blood in these cases showsa polycythemic picture, which they believe to be due to interference withthe proper pulmonary exchange of oxygen, resulting in a low tension ofoxygen in the arterial blood which in turn overstimulates the bone marrow.The usual response of the blood to low oxygen tensions obtained for shortperiods under experimental conditions has been studied extensively. Butinvestigations of the changes occurring in cases of chronic pulmonary dis-eases with or without anoxemia due to faulty pulmonary exchange are notavailable except in a few isolated cases. Wehave attempted to clarify thisproblem by studying a group of cases with chronic pulmonary diseases;determining not only the characteristics of the erythrocytes and the bloodvolume but also correlating these findings with various factors such asarterial oxygen saturation, the pulmonary capacity and its sub-divisionsand the duration and severity of the disease. We feel that these observa-tions of the volume and morphology of the blood are enhanced by otherstudies, to be reported later, which we have made on these patients in orderbetter to classify and understand their functional pathology.

Well established standards of the normal morphology of the red bloodcells are available in the literature, but the values for the blood volume re-ported by different observers, using similar technique and experimentalconditions, vary markedly. Wehave collected in Table I the values for

1 The expenses of this investigation were defrayed from a fund contributedby the Corning Glass Company, The Eastman Kodak Company, The AmericanGrinding Wheel Manufacturing Association, The American Laundry Ma-chinery Company, The Gleason Works, The Symington Company and thePfaudler Company.

2Travelling Fellow of the Rockefeller Foundation; Fereday Fellow, St.John's College, Oxford.

999

1000 BLOODVOLUMEIN RESPIRATORYDISEASE

| E -l - MOb e .o 0S

14 W4. .; .+cb.

43iNE Et- o i0k

10

o

04

V ~~05

R > E~M3 E it EW e

4

V ci~0 ie- 4M, c.

00

CDs8 s S

..~~~~0-0 0

oNO00C -0

.0~~~~~~

N. L. KALTREIDER, A. HURTADOAND W. D. W. BROOKS

the plasma and blood volume in normal male subjects reported in theliterature, including only those reports dealing with the larger number ofcases. All these determinations, in normal male subjects of various agegroups were made by injecting a dye into the peripheral blood stream ac-cording to the method first introduced by Keith, Rowntree and Geraghty(7). The plasma volume has been variously estimated from 34 cc. to51 cc., per kilogram and the volume of blood, from 72 cc. to 89 cc. perkilogram of body weight. Fleischer-Hanson (8), who objects to theabove procedure because of inadequate mixing of the blood and dye inthe time allowed, has the subject perform the so-called " mixing move-ments " and finds the volume of the blood as low as 49 cc. per kilogram.Because of this wide variation it was felt necessary to determine our ownstandards for normal individuals in order to have a basis for evaluatingour study of pathological cases. A review of the literature also indicatesthat one must allow generous limits for normal variation.

METHODS

In this investigation the dye method of Keith, Rowntree and Geraghty(7) with the modifications as described by Hooper, Smith, Belt andWhipple (9) was used for determining the plasma volume. All the ob-servations were made with the patient in the recumbent position, followinga fast of twelve hours. A needle was inserted into the antecubital veinand 12 to 15 cc. of blood were removed without stasis. About 3 cc. of theblood were placed in an oxalated tube for hemoglobin determination, whilethe remaining 8 to 10 cc. of blood were placed in a centrifuge tube accu-rately calibrated to tenths of a cubic centimeter and containing 2 cc. of1.6 per cent solution of sodium oxalate. The tube was stoppered andinverted several times to prevent clotting. Without removing the needlefrom the vein, a 1.5 per cent solution of brilliant vital red, freshly pre-pared and filtered, was injected into the blood stream. In each case fourmilligrams of the dye per kilogram body weight were introduced. Fourminutes after the injection, 8 to 10 cc. of blood were removed from theantecubital vein of the opposite arm. This blood was placed in anothergraduated centrifuge tube containing 2 cc. of 1.6 per cent solution ofsodium oxalate. This was stoppered, inverted and, along with the othertube, was centrifuged at 2700 revolutions per minute for 45 minutes.Then the hematocrit and other readings necessary for the calculation ofthe plasma volume were made. The standard, made from the filteredsolution, and the unknown solution were then prepared for colorimetriccomparison. The volumes of the plasma and blood were calculated ac-cording to the formulas derived by Hooper, Smith, Belt and Whipple (9).In all cases the hemoglobin concentration was determined on the firstsample of blood by measuring the oxygen combining power according to

1001

BLOODVOLUMEIN RESPIRATORYDISEASE

Van Slyke's method (10). It is possible to calculate the corpuscular vol-ume and hemoglobin per 100 cc. of blood. Wehave not encountered asingle reaction to the injection of the dye in 55 determinations.

The oxygen content and combining power of the arterial blood weredetermined in the Van Slyke manometric apparatus.

The total pulmonary capacity and its sub-divisions were measuredaccording to the methods used in this clinic (11, 12).

DETERMINATIONSON NORMALSUBJECTS

The volumes of the plasma and blood were estimated on 25 normal malesubjects, who were students in this University. No selective criteria asto physical characteristics were used save that the subjects were free fromany discernible disease. A clinical history was obtained from each indi-vidual and a physical examination made.

The physical characteristics and the values for the blood volume and itscomponents of these subjects are summarized in Table II. The weightobserved in this group corresponds closely with the average ideal weightcalculated from age and height.

TABLE II

The volumes of the plasma and blood in 25 normal males with age and physical characteristicsof the subjects

(Dye method-Brilliant vital red)

Standard CoefficientMean dvain of Rangedeviation variation

Age, years ................. 26 d .31t 2.26-1 .22t 8.7 22 - 32Weight, kgm....... 76.2 :+ 1.22 9.071: .87 11.9 60.6 - 104Height, cm....... 178.2 :1: .55 4.07 41 .39 2.3 170 - 186.5Surface area, square meters ... 1.93 4 .02 .1114 .01 5.7 1.73- 2.19

Plasma volume, liters....... . 3.22 4 .06 .42:1: .04 13.0 2.21- 4.06Plasma/kgm .. ............ 42.8 :1: .59 4.4 =1 .42 10.3 34.7 - 50.3Plasma/square meter, liters;. . 1.694: .02 .171: .02 10.1 1.28- 1.88Blood volume, liters ........ 5.934: .10 .771: .08 12.9 3.95- 7.49Blood/kgm., cc .............. 79.1 14 .97 7.191: .69 9.1 62.1 - 91.1Blood/square meter, liters.... 3.10=1 .04 .30+ .03 9.8 2.28- 3.42Cell volume, liters . ........ 2.6941 .05 .3941 .04 14.5 1.66- 3.38Cells/kgm., cc .............. 35.8 4 .49 3.62=1 .06 10.1 26.0 - 44.7Cells/square meter, liters . . . . . 1.404: .02 .161: .02 11.4 .96- 1.68Total hemoglobin, grams..... 982 4:20.2 149.9 4:14.3 15.2 590 -1216Hemoglobin/kgm., grams..... 12.9 .1: .20 1.47 i .14 11.3 9.3 - 15.3Hemoglobin/square meter,

grams .................. 499 -4- 8.8 64.9 1: 6.2 13.0 341 - 590Hemoglobin per 100 cc., grams 16.2 4: .11 .84-1 .08 5.1 14.9 - 17.7Plasma, per cent .......... 54.3 .1: .32 2.381: .23 4.3 47.9 - 58.4R.B.C., per cent ......... 45.1 -4- .31 2.29-4 .22 5.1 40.9 - 51.3

$ Probable error.

1002


The mean value of the plasma volume was 3.22 liters with variationbetween 2.21 and 4.06 liters, while the plasma per kilogram of body weightwas 42.8 cc., a value just about midway between the lowest and the highestvalues reported in the literature.

The blood volume was observed to vary markedly both in total volumeand volume per kilogram of body weight. The mean value of the formerwas 5.93 liters varying from 3.95 to 7.49 liters, while that of the latter was79.1 cc. with variation between 62.1 and 91.1 cc. The mean value forblood volume per kilogram of body weight was again found to be aboutmidway between the extremes in the literature.

The total volume of the cells and total hemoglobin varied markedlyfrom individual to individual. The mean value for the cell volume was2.69 liters while the value for each kilogram of body weight was 35.8 cc.The mean value for the hemoglobin per kilogram of body weight was 12.9grams, a figure almost two grams lower than that reported by Rowntreeand Brown (4) in a similar group of cases.

The mean value for the red blood cell percentage was 45.1 with varia-tion between 40.9 and 51.3. Determinations of hemoglobin per 100 cc.of blood gave a mean value of 16.2 grams. These results correspond veryclosely with those collected from papers in the literature and reported byWintrobe (13), who found in 381 cases (all males) that the average valuefor the hematocrit was 46.3 per cent and in 583 cases the hemoglobin per100 cc. of blood was 16.0 grams.

The correlation of the blood volume and its components to body weightand body surface area is given in Table III. The most significant corre-lation exists between the body weight and the volume of the blood and its

TABLE III

Coirreltion of blood volume with various body measurementsCorrelationcoefficient

Total blood volume to body weight ........................ .7297 - .0631Total blood volume to surface area ......................... .6756 + .0733Total plasma volume to body weight ....................... .6954 + .0697Total plasma volume to surface area ....................... .6387 4 .0798Total cell volume to body weight ........................... 8014 .0483Total cell volume to surface area ........................... 7840 1 .0519Total hemoglobin to body weight ........................... 7700 4 .0549Total hemoglobin to surface area ........................... 7648 4 .0560

$ Probable error.

components. This finding indicates that knowing the body weight of anindividual in kilograms one can predict the total blood volume with a fairdegree of accuracy by means of the regression formula derived from thecoefficient of correlation.3 From the predicted blood volume and the nor-

3 The regression formula is:Total volume= (Kilograms body weight X 0.06) + 1.41.

1003


mal mean values for hematocrit and hemoglobin per 100 cc. of blood, onecan calculate the expected cell and plasma volumes and the total hemo-globin. Rowntree and Brown (4) found the best correlation betweensurface area of the body and the plasma and blood volume.

The total plasma, blood and cell volume and the total hemoglobin ofthe 25 normal subjects were calculated from the regression formulas andcompared with the observed values for the purpose of establishing thenormal range of variability. Of the observed blood volumes 92 per centfell within the limits plus and minus 15 per cent of the calculated values;while of the observed plasma and cell volumes and total circulating hemo-globin 88 per cent were within this same limit. Individual variationsaround plus and minus 15 per cent of the calculated may not be significantbut when the mean value for a group of pathological cases approaches thislimit, the difference becomes of some importance.

DETERMINATIONSON CASES WITH CHRONICPULMONARYDISEASES

LiteratureBlood volume determinations have been made both by the carbon mon-

oxide and dye methods on patients with chronic respiratory diseases. Infive cases with chronic bronchitis, emphysema and asthma, studied byPlesch (14) the average blood volume by the carbon monoxide method was72 cc. per kilogram of body weight. This was 35 per cent greater thanthe values which he found in nine normal subjects. These values are ofcourse low when compared with those that one obtains by means of thedye method; a difference found repeatedly by many investigators. Uhlen-bruck (5) using the dye method (congo red), confirmed the results ofPlesch. He estimated the volume of the blood and plasma in 7 normalmales and found mean values of 79.6 cc. and 41.4 cc. per kilogram of bodyweight respectively. In 8 male patients with emphysema and asthma thisinvestigator found an average blood volume of 101 cc. per kilogram ofbody weight with extreme variations of 78 and 147 cc. and an averageplasma volume of 53 cc. per kilogram, an increase in blood volume of 27per cent and an increase in the plasma volume of 28 per cent. Lemon(15) reported 12 cases (11 males and 1 female) with pulmonary emphy-sema, in which he determined not only the volume of the plasma and bloodbut also the arterial oxygen saturation, the vital capacity and the character-istics of the erythrocytes. He found that the mean value for the bloodvolume per kilogram of body weight was only slightly higher (4 cc.) thanthat of the normal group. In several cases there was evidence of increasein the concentration of the blood, i.e. increase in the volume of cells with-out increase in the blood volume. Along with the concentration of theblood he observed a definite increase in the hemoglobin content of theerythrocytes. Arterial blood was obtained in 7 cases and, in all, the satu-

1004


ration was less than 95 per cent. No correlation was demonstrated be-tween the decrease in the oxygen saturation of the arterial blood and thealterations in the blood volume or between decrease in vital capacity andchanges in the blood volume. None of the cases which he studied simu-lated polycythemia vera. So far as we can find no one has reported deter-minations of blood volume in a group of cases with pulmonary fibrosis.

Material

Determinations of plasma and blood volume and morphology of thecells were made in 16 cases with chronic pulmonary emphysema and in14 cases of pulmonary fibrosis. The major purpose of this study was toattempt to correlate these findings with the clinical condition of the patient,the oxygen saturation of the arterial blood and the pulmonary capacity.

Emphysema. The 16 patients in this group had varying degrees ofemphysema associated with chronic bronchitis, bronchiectasis or asthma.The physical characteristics, symptoms and signs, with interpretations ofthe roentgenograms of the chest are given in Table IV. The age of theindividuals varied from 31 to 59 years. None of the patients was par-ticularly obese; many of the subjects weighed less than their "ideal"weight calculated according to the height and age. The average weightof the group was 6 kilograms below that of their " ideal " weight. All ofthe patients except one complained of cough. Dyspnea was a symptomof all the subjects, and in two it was present during rest. All but threehad asthmatic attacks. The duration of the symptoms varied from 1 to25 years. None of the patients complained of nervous or psychic symp-toms. Cyanosis was observed in half the cases; clubbing of the fingerswas found in 6 of the 16 subjects. The spleen was not palpable in anyof these individuals. The degree of emphysema was estimated from therelative values of the residual air and the total pulmonary capacity. Theblood pressure was within normal limits in all subjects. The electro-cardiogram was normal in all except Case 1, in which there was evidenceof myocardial damage, and in Cases 13, 14 and 15, in which left ventricularpreponderance was indicated.

Fibrosis. In 10 of the 14 cases, the fibrosis was suspected to be dueto inhalation of silica. The etiology of the fibrosis in the remaining casesis not known. One patient had arteriosclerotic heart disease which waswell compensated at the time of the examination; another, Case 22, had asecondary anemia. The clinical observations in this group of patients aresummarized in Table V. The age of the subjects varied from 32 to 65years. The average " ideal " weight of the group was 68.6 kilograms ascompared with that of the observed which was 67.7 kilograms. A highpercentage of the patients complained of cough and dyspnea, while onlytwo of them (Cases 19 and 24) gave a history of asthma. The duration

1005

1006

be

._

11


*4

.0

a.,0"A

Cd

c4

'0

bO

0

n

cecd

-

._m

N)Cd0 b.O

Qr._ =..-,n,0 4.J

be0

¢i 24-4

. 0

4L)

_

*w.._4-

4i

ba

. -4

-40

_..q

'04-)

0I

_ 0Coa o Cd

-4)

C:

4-

144

4)

w

E4

E4

U;

b.

-

4-

._

0C)

cn

4- bI-

4.4

c44

0

4:-44

bII.e

bO'Do: .Sw r.

4)4

co :1

.°-

0O.wco

C) X4) x E=*

+ + +'Y + + \+ + + y+ \+ +

E4. + + + + + + +

o + +

'V. +

CU.

X + + + + + i+ + +0+}° +S1 + +s +> +> ±

Oo+1+

13!R + ++ 1+ +s +

+ + + -b++1 + + + + +

+ +~~+ + + +U~~~~

+~~~~f f f

0 +~~~0 0

I) 00~~~~~~~~~~~~~0v

coC-)

1j 1

I,

04

e

m>1

X

I.

Qo

Un0

U)._;t2

lc4.4

4d00

0-4

4-J

a4)

04Ibro

0OU

*

Io*

N. L. KALTREIDER, A. HURTADOAND W. D. W. BROOKS 1007

bO %04 be r. CIObO 3.4 0biO 4i.0 54,

COCd biD Cd li-4i E Z W biOE Cd biO4i 1.0 4-i c Cd

OD cd Cd co biD

bO 4) 0 bOZ biO 0 W co9. biO4-) Ei - W 0

0.0Cd 0 .0 0 biO -0 W 1.1 O.ed Cd O 4jbiO Cd .-.a bO biDCd r_ 4) Cd V r Cd 'CdLd bO biO cdbO >, cd

Cd 0 r CO 0 4i co 4ied b,0 biO q*-4 0s. -- Cd-cd x 0 (D 0 cd 0x cd Cd la s 4i bio c: x

Co C biDCd r. 1.0 4i Cdb 0 W"

Cd r ..*

Cd Cd co co Cd Cd Cd coco Cd

0cd to td cd Cd 5, cdb x u x Ei 0

co too OW ow Ei $04 Ei<

txi 4)W,... >,

00.6 0 bW 0

rA W co W (a to1.4 W U4 W U4 Lo

Cd Cd co Cd Cd Cd0 a

S>.


ICa

a).WbCa

0 blO.-

11*4Ca

C)

.

Coa

C

*_)01) v bi

._ A

(d cd =

0

.0 bOO9 Cd1

bCoco

a .tb

IID,= .

'.

Ca CO

-1 0-

wCo.i

1.II bO$C. .-

CO--Caq. , gn

C) C: Caa._ ._

4C0

=0

Ca-.

._ _

0~ 4i 0 oCL.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.

0C Ca.0~~cdCd CodO4*CaO bO

:3 0.00.0a

Ca

eq

C)al)

Ca

a)

C~4

Ca

a)

'.4

Ca

aL)

cd

Ca

14)

0~~~ ~ ~ ~ ~ ~ ~

blo blobiCa CAa) a) U2'

mCa~~ ~ o ~~oCa'.4-~~~C

0 ~~~~~Ca - Cau _ _ _ _ _ C/)~ cr)

+ ~+ + + +Ca+ 0 ~+ +++ +

~~4 + +

+ ~~~~~~~+0 + ++

+5+4J 0 ~ 0 00 1

~~ U) 00 00 C-- Cli~ 4 j 4 ~ 4 ~ f

00 0t C

v

Ca

U

1eq

1008

4i. 4.

i

HtoF.

ICa

o

ItI1*Cb

v.0

b 01

I,%-.

00 0


n

._

*a

4A

.0to0

4.-=o c.5

4.,)44

0-44-'-0).0

4.d 4J

00u

o_ .44.O +- 4).

44 44 4- @4

C z a,M

00.0 .- co

b0 4 10U4 4 ~R 4

4-

dOIL.*-

.0

'e 1

8 Cb0.la0-'-

9 U 4-'w b044-r .. .0

b0

.0-

.0c' o

444o0.0104.,o =

YJ w

F;2

.0bCO4:014

. 0

w :=

4D.U

b=ob4.444-' 4-'

4)0%4)4

4.~= 9c: =. 0*4-'o _JIC: bo

0w

0 04 E4.4 ).0" .CQ

_{(.

'04L)44i4-' U)

bCt0 *Uce wCd o

Ei=1 0

1: _

U)U) ~ U) U) U)

co 0 0 0' 0 0 0 04. 4. 4.0. 4. 4. '-.4.~~~~~~~~I.

o~~~~~~~~~~~~T

.2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~4

Cd4_ _ _ _zco

cd 4J U)M~~~~~~~~~~~~~~~~~~~~~~~~~~U4) 0 4) 4) 4) c2d' 4

0 0~ ~~ ~~0 ii +

1z +0 b

0 cd~~~~0a~~ ~ ~ ~ ~ *.-0

S 04) >)

').5' 04.0) 4

~~~~~~~ bO ~ t. bi,U) 4

00

.0 +~~~~~.0CC0 + + 0 +4 +O0)

+ _i

.0 0+)0 0 1

06 00 ~ 06 0' 0U4) '0 -4 44 0 0

41)~~~~~0be 0011

U

I.

04

0


of symptoms varied from 3 months to 12 years. The duration of ex-posure to silica in the patients suspected of having pneumonokoniosisvaried from 7 months to 25 years. One pafient (Case 28) complained ofmuscular pains and dizziness. Cyanosis was observed in half and clubbingof the fingers in 3 of the 14 cases. The blood pressure was within normallimits except in Cases 19 and 30 where it was 140/100 and 160/105 re-spectively. Electrocardiograms showed left ventricular preponderance inCases 17, 18 and 26 while a preponderance of the right ventricle was foundin only one (Case 17). The spleen was not felt in any of the subjects.

Results

Emphysema. In Table VI are presented the individual and the meanvalues for the total volume and the volume per kilogram of body weightfor the blood, plasma, cells and circulating hemoglobin. The total bloodvolume varied between 3.18 and 7.27 liters with a mean value of 4.87liters. The mean value of the blood volume per kilogram of body weightwas 76.7 cc., a figure somewhat below that of the normal subjects. Theextremes were 68.4 and 91.6 cc. All the observations fell within normallimits as shown in Figure 1. The mean value of the plasma volume perkilogram was slightly below that of the normal, 40.7 cc. as compared with42.8 cc. On the other hand the mean value of cell volume per kilogramin the pathological cases was 35.5 cc., which was approximately the sameas that of the normal group. Only two observations were slightly out-side the normal limits as shown in Figure 1. The mean value for thehemoglobin per kilogram of body weight was 12.5, slightly below the nor-mal; with 2 cases beyond the lower limits of normal. (Figure 2.) Thehemoglobin per 100 cc. of blood varied between 11.6 and 18.7 grams witha mean of 16.2 grams, which is identical with that of the normal. Thehematocrit readings of cell volume also varied markedly between 38.5 to52.6 per cent with a mean value of 46.3 per cent. We find then, in thisgroup of cases with emphysema, a slight though not significant decreasein the blood and plasma volume and the hemoglobin per kilogram of bodyweight, while the cell volume remains the same.

Fibrosis. The results in a study of 14 cases of chronic pulmonaryfibrosis are tabulated in Table V. In this group we find a definite increasein the mean values of blood and cell volume per kilogram of body weight,the former mean value being 88 cc. as compared with 79.1 cc. of the normalgroup; while the latter value was 45.2 cc. compared with the normal valueof 35.8 cc. It is evident from Table VI and Figure 1 that the mean valuesof the whole group are high due to marked increase in the volume of theblood and cells in three (Cases 19, 27 and 28) of the fourteen cases whilein the remaining ones the values obtained were within normal limits. Themean value for the plasma volume was 42.4 cc., approximately that of the

1010


0%toU)

e4a-)-H%0

00

* ** -H

- - --- -- --- U)

Oeq oeqt-ooc ceqq -HV

" 4 O O " " o0U) 4-4 eOO t

lw 00 -) -0 N" 00 so C4 - 0%ul)

w~ 0

00

C~ _ _ l OI _~ 4R _1_ _~ t-~ t'- -vo \0 \0! (7 oL.-e) \o \Og oo o0 os I

0%0%0\6 -H

0ooM~ ~ ~

e00 00 \0 o o U) \0 0o \ os 00o \os U) vo tl

eqvo '0 o4 u) o 00 e r- 0% 00 '00 i -'be ('_flvC ) )*oe_eo

_ CS N _e N e e n CU

'0000%000q 0 0 a) % 0 O'P_eq 0% V. z- oo oeq 0% 0% 0% '0f '00 t-' 00.. . . .. . . . 11-r b e ~~~~~~~~U) ou ov so

a)eq N %0 U) e i-a _ eq a-) %x a' - *4 *O- 0%

t-.000000 0'0o0 0t~

a0) O) 4o "f'0 ) inOf) £. u) + u) 9 b

C, Uz 4 e6 e; 6o "i ( ei t.. N6 4 u)i N 4 4

*0

coeq

oo.I - I LI -I___ __ _ __ _ __ _ __ _ ± ____

- eq Mf) an'o0 00% 0- eq ) -,ja a)'O_-_ _I - _

'0

la-=0

cd'_ 0

010.

:4

1011

0,u e

bre08

;:54,

ogS. 0

S:,

a

4 3 4)

d

4,

8

4, pg

0

0

4,

v

4*w

4,

4,

a

0

0

in

U).40

0

4,

'I1010

'0100:0

0'

a-aV

(.4

-HU)

00

-H

(.4co

-H

_0'

0a

(.4

-H

0'

0'V

00(.

^0

-H

*

0'U)

0atoa,

J.,

24)

a'a

4,0

U)

d0

4.)4CdP._

la-Cd

C12*

eq r- C4 J... %O .4d4 * 1'.. 9-4 t- In t- t- " In 0.'r; . 0,; 4 C4 0. c4 06 . o6 1 ; 4 ui -.4 06W44 .4t to to IRV lqt m .4d4 lot 14* in Ild4


000 w z - ,.400 f 0 to t- 00 4 eq" Uf)u f q44 IR 14 14 q4 if+ 4 in'0zo I f)

'0OX-oo.r-

C4o4*

Ui)00oio

00

9 00

C 0 f) 0% t00% 000oC)) 0 If) "0. +0

04

00 '0

*.0%~f)~-400I#)I%1 -H -

-- _Io4' ---- eqei - t- >_ If

' '00

q -s

s(7.it-C) o (D, 00%O%-,0i

If eq

CK t- U) m- 0~ 00" n C) Olm -H -

eq eq 00 00 0 bj e0 \0 Z I) - if) '0 -ov

-H 41

If 0%

No t- 0~ '-'NO 00 0) 0%'40'0 0% UU

in I" va I4 m m q4 l e 010*e e' 00

- '0'0

0 0 0% "%'0 0000 0' 0ev0 '0 lf)t

- v-o6) 0

eq eq'0q0IfIf'- 4

eNNS N>NeXe ee e 00 eq

_+ fio N N e

00N 00 mU

I oo0 _- o o'-14 --' " I " O N0% t~- l If) WI) WIf) WIf) Q0 I- co 14*

~6 u' uif C4 4o4 i '06 i t 1. uif)'_O>b+OsuauouZu)soOroO~m-

1-00

408o6

If)No

UiI

-I;

4- 00 0% o q )4 ) '0%O - 00 0% 0- _ q eqe4 q q e eq e e eq eq" f

'0

ro .

G

C3

la

co w

040

0...0)

.4046 2 l

1012

4)

.0A

.0

be

S04):Ui

4)

[UH0

0W

0

-4c4

4)

0uz

4)co

10co104)

'0coI

I

d4

0%

I4-H

-H

-Hco

0%

e4

41

-H

1400

r

0%

41

-H

o0

'Ioo)o%I'-H

eq

eq

I'U)

0

214)

Ht<90o

P340

1:1.4

Xco4)

I


130 qo 2?

120 so 2

fie T0 21

0 5~~~690 so

90 20

00

--.0~-

70 30

0 0~~~~~~~0

60 *2 0

C.C. C.C. GMS.

~~~~~~~~~~~3

FIG. 1. DETERMINATIONSOF BLOODAND CELL VOLUMEAND HEMOGLOBINPER KILOGRAMOF BODYWEIGHT IN 30 CASES OF CHRONICRESPIRATORYDIS-EASES.

The mean values for the normal subjects are represented by the unbrokenlines, while the broken ones show the deviations from the mean. Circles indi-cate cases with emphysema. Dots, those with fibrosis.

1. Blood volume. 2. Cell volume. 3. Hemoglobin.

75 23

29. 23

21~~~~~0

oIf

MILION5PE CET

FIG. 2. ERYTHROCYTECOUNT, HEMATOCRIT, AND HEMOGLOBINPER 100 CC. OFBLOODIN 30 CASESOF PULMONARYEMPHYSEMAAND FIBROSIS

1. Red blood cell count per cubic millimeter.2. Hematocrit.3. Hemoglobin per 100 cc. of blood.

1013


normal group. Although the values for the hemoglobin per kilogram ofbody weight varied widely, the mean value was 2 grams higher than thatof the normal subjects. Here again Cases 19, 27 and 28 were definitelyabove the normal limits while Case 22 was slightly below, as illustrated inFigure 1. Likewise the mean value of the hemoglobin per 100 cc. ofblood was somewhat above that of the normal group, while in the samethree cases mentioned above the hemoglobin was elevated. Along withthe above findings we found the mean for the hematocrit somewhat in-creased, 49.7 per cent as compared with the normal of 45.1 per cent, while6 of the cases showed-an abnormally high value (Figure 2.)

The calculated values based on body weight, and the observed valuesfor the total blood, plasma and cell volume and hemoglobin in the 30pathological cases are represented in Figure 3. This shows graphically

7 9 to It 12 13 Is

49 20 22 23 22 26 16 27 28 2X

FIG. 3. CALCULATEDAND OBSERVEDBLOODVOLUMEIN CASES OFPULMONARYEMPHYSEMAAND FIBROSIS

Cases 1 to 16 inclusive are those with emphysema; from 17 to 30 inclusive,cases of fibrosis. Each case is represented by two columns. The one on theleft, with broken lines is the predicted while the right hand column is the ob-served volume. The white area is plasma; the black, cell volume while thetransverse lines represent the total hemoglobin.

that there are no significant variations in cases of pulmonary emphysema(Cases 1 to 17) while in the group with pulmonary fibrosis Cases 27 and

1014


28 show evidence of hydremic plethora 4 and Case 19 shows an increase inthe blood and cell volume and hemoglobin while the plasma is slightlyreduced.

When the two groups are taken together we find that the mean valuesfor the blood and cell volume, the total hemoglobin and the hematocrit areslightly above those observed in the normal subjects, while the plasma vol-ume is slightly decreased; thus showing slight concentration of the blood.

The mean values for the blood, plasma and cell volume and circulatinghemoglobin expressed in terms of cubic centimeters per kilogram of bodyweight for the three groups (normal, emphysema, and fibrosis) are com-pared graphically in Figure 4. A slight decrease in the blood and plasma

FIG. 4. MEANVALUESFORTHE BLOODVOLUMEAND ITS COMPONENTSPER KILOGRAMOF BODYWEIGHT

volume is evident in the cases of emphysema while the cell volume andhemoglobin are practically identical with the normal group. On the otherhand, the cases with pulmonary fibrosis show an increase in mean valuesof 11 per cent in the blood volume, of 26 per cent in the cell volume andof 15.5 per cent in hemoglobin as compared with the normal, while noabnormality in the mean plasma volume was observed.

4 Same as polycythemic hypervolemia used by Rowntree, designating increaseof the volume of blood and cells above the limits for normal individuals.

'0

so

70.

9 6~~~~~~~~~~~~~~~~~0'4

-IaL.

a~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~>40I.-0~~~~~~~~~~~~~~~~~~~~3

1--~~~~~~~~~~~~~~~~~~~~~~~~1

30

NOMLEPYEAwRfSSGS

1015*^w


RELATIONSHIP OF BLOODVOLUMETO VARIOUSFACTORS

Duration and severity of symptoms. Those cases which showed an in-creased blood and cell volume had moderate or severe respiratory disability,but not all the patients complaining of marked dyspnea and severe asth-matic attacks showed abnormality in the volume of the blood. No definiterelationship could be demonstrated between alteration in the blood volumeand duration of symptoms. For instance, in Case 27 who had had symp-toms for only one year, a blood volume of 108.5 cc. per kilogram of bodyweight was found.

Arterial oxygen saturation. The carbon dioxide and oxygen contentand oxygen combining power of the arterial blood was determined in 22of these cases. All except 6 were found to have an oxygen saturation lessthan 93 per cent, with extremes of 67 and 98 per cent. The oxygen satu-ration in Cases 19, 27 and 28 which showed an increase in blood volumewas found to be very low, 80.6, 67.2 and 81.1 per cent respectively, whilein Cases 1, 2, 3 and 11 in which the arterial oxygen saturation ranged be-tween 74 and 84 per cent there was no increase in blood volume. In thegroup of cases in which the arterial oxygen saturation was below 90 percent, the blood volume per kilogram body weight was increased as shownin Table VII.

Pulmonary capacity. That no relationship exists between decrease invital capacity and changes in the blood volume, hematocrit and hemoglobinis shown in Table VII. The decrease in vital capacity varied between 16.5and 71.8 per cent, all values being beyond the limit of normal variationwhich is considered to be 15 per cent. No correlation was found betweenthe ratio of residual air to total pulmonary capacity and alterations in theblood volume or any of its components. The ratio varied between 23.6 and73.4 per cent with only 8 cases or 35 per cent within normal limits.

CHARACTERISTICSOF THE ERYTHROCYTES

Very few studies have been made on the characteristics of .the redblood cells of patients suffering from pulmonary emphysema and fibrosis.In 22 cases of pulmonary emphysema Price-Jones (16) found the size ofthe red cell larger than in a corresponding group of normal subjects usedas controls. The mean diameter of the erythrocytes in the former groupwas 7.69 ,u while in the latter it was 7.24 , an increase which the authorbelieved significant. Lemon (15) found an increase of 20 per cent in thecorpuscular hemoglobin in 12 cases of chronic pulmonary emphysema,while the volume of the individual cells was not significantly increased.The average number of red blood cells in each cubic millimeter was 5.02millions with a range between 4.05 and 6.86 millions.

The results of a study of the characteristics of the erythrocytes in 36cases of pulmonary emphysema and fibrosis are summarized in Table VIII.

1016


000.0

E 008 No 0<m

"~ ~~"3

%0 00 C48 L' 0. 06. .4 uif

~0

:3 o Q oO

.E E.A

` 0Q \+W a

E .8 o o

34W eq Ot-m CS

3S mooo- -r-

I. ow o )

Io .o

r-0 C~ 00 0

z

o

~~: ~~~01')t


I.Z401..

a.X

'Z1

I-

I

t,~1

I

gco

CO.

06

aD0

U

o~~~~o-H

0

U)

0

C;

oo'0

-H

U)

00

00

0%

U)%0eq

-H

0.lt i!o c!e; tz e°C*S- .5 t 0 0 - '

0 -

0 '0 U)

NO

0 00 U)*u J

.0 X' Ne eq

az -H -H -H -H00 in 0% qd4

00 eq U

.v .5 %0U~

00 ~ 00 ) '0~

0% i- 00-

ODeq0 00 e

0O

F)

%4

I-

09UA

i-:5 -0 -

.Ei -

CIS :

0 -

^ Xu

r,

bO0wc-a

c).0= a5? 80 0a, 0

8. U0o:

o~~~~~cIn.0

0o

aN

U)

0

CU

5

0

a-i

co

bCU)

m

0

0

Cq

rCU)

CU

0

0

00

U)

CU

a)

a)C

1018

t o%) 4t; V.

IC


The blood volumes of 30 of these cases are reported above. The meanvalue for the number of red cells per c.mm. in both groups was 5.70 mil-lions, a slight increase over that of the normal (5.50 millions) calculatedin 352 males reported by Osgood (17), Wintrobe (18), and Foster andJohnson (19). The mean value for the group with emphysema was 5.39millions a figure slightly below the normal value while that for the groupwith fibrosis was 5.87 millions, which is definitely above the normal. Theextremes in the two groups were 4.2 and 8.17 millions. As illustrated inFigure 2, an equal number of cases fell below as above the limits of normal.

The corpuscular volume for both groups was increased, the mean valuebeing 86.89u8 for the cases showing emphysema and 83.59,u8 for the groupexhibiting fibrosis, while for the whole group it was 84.59,u3 (normal value82.2 cubic microns).

Correspondingly, the corpuscular hemoglobin for the cases with fibrosiswas slightly lower than for those with emphysema, having mean valuesof 27.9 and 30.1 micromicrograms (gm. X 10-12) respectively. (Normalvalue 28.8 gm. X 10-12.)

As shown in Table VIII the mean for the corpuscular hemoglobin con-centration in both groups was identical with that of the normal. The meanvalue in cases with emphysema was slightly above, while in the group withfibrosis it was just below the normal value.

TABLE IX

Relation of the number of erythrocytes to their size and hemoglobin concentration

NumberHemo ~~~~~~~~~Corpuscular

Number Ca em globin Corpuscular Corpuscular| hemoglobin of rederofzrs Cases 100per volume hemoglobin concen- ceollerythrocytes 10c.timtion hemalcri

miliox grams cubic microns grams X 10-12 per cent per cent4.5 5 15.1 93.3 30.4 32.4 44.55.0 11 16.2 88.8 31.0 34.9 46.35.5 11 15.7 81.2 27.3 33.6 46.86.0 3 16.8 81.4 28.0 34.5 49.16.5 3 18.3 74.3 26.8 36.4 50.7

Table IX shows the variation of the cellular characteristics, hemoglobinper 100 cc. of blood, and the hematocrit in these cases according to the redcell count. Here was found the inverse correlation of the corpuscularhemoglobin and volume to the red cell count, such as occurs in normal sub-jects; in other words as the red cell count increased the cells became smallerand contained less hemoglobin; both of these changes being proportional,the corpuscular hemoglobin concentration remained the same.

1019


DISCUSSION

Investigations of the blood volume in cases of chronic pulmonary dis-ease are important from the standpoint of the various theories advancedto explain the production of polycythemia and its relation to a low oxygentension. The development of these ideas is closely correlated with andbased upon observations made at high altitudes, or in chambers where thebarometric pressure is lowered to simulate the effects of higher levels. Abrief review of the results obtained by such investigations will be usefulin understanding the present status of the pathogenesis of polycythemia.

Since the discovery by Paul Bert (20) in 1882 (confirmed a few yearslater by Viault (21)), that the blood of animals living in the PeruvianAndes has an increased number of red blood cells and an increased capacityfor combining with oxygen, practically all investigators agree that such achange occurs both in animals and man at low barometric pressure, al-though its intensity varies markedly in different individuals. Miescher(22) in 1893 formulated the theory that oxygen deficiency in the bonemarrow was the stimulus for the formation of new red cells. His ideahas had general acceptance and was substantiated indirectly both by thestudies of Bence (23) who claimed that inhalation of oxygen decreasesthe erythrocytosis which one encounters at high altitudes, and by the ob-servations of Dersca and Valter (24) who succeeded in decreasing thenumber of red cells in the peripheral blood of patients with anoxemia bythe intravenous injection of oxygen. The work of Barcroft and his co-workers (25) demonstrating that the spleen is a storehouse for red cellswhich are liberated and thrown into the circulation in conditions of oxygenwant, has thrown new light on the explanation of erythrocytosis at highaltitudes. At the present time most observers agree that this increase inred cells and hemoglobin is primarily produced by the contraction of thespleen, liberating the red cells stored in its pulp, and possibly also byreleasing the supply of red cells stored in the bone marrow (McNee (26) ).Secondarily, if the condition of oxygen want persists, signs of bone marrowactivity appear and the increase in the number of red cells may then becorrelated with the signs of overactivity of the hematopoietic system.However, because so few estimations of blood volume have been made,it is still a debated point whether this erythrocytosis in new comers andresidents at a high altitude is associated with a real increase in the totalvolume of blood cells or with changes in their concentration in the blood.In 1910 Douglas (27) made observations by means of the carbon monoxidemethod on Teneriffe (altitude 7,000 feet) and was unable to detect anychanges. The Pike's Peak Expedition (by Haldane and others (28))found evidence of a temporary concentration of red blood cells during thefirst few days and later a true increase in the total volume of cells. Smith,Belt, Arnold and Carrier (29) found minimal changes in the blood volume

1020


after a brief stay at Long Lake in the Sierra Nevada Mountains (altitude11,000 feet), and Lippmann (30) and Laquer (31) found very slightalterations at Davos (5,100 feet). Monge (32) has described the exist-ence of a primary polycythemia in the residents of the Peruvian Andes, butstudies of the blood volume have not been made in such cases. It is evi-dent from this review that our knowledge concerning the true nature ofthe erythrocytosis that man develops at high altitude is insufficient.Whether or not there is an increase in the blood volume similar to thatfound in cases of polycythemia vera at sea level is not known. Furtherstudies in this connection will undoubtedly help solve this interestingproblem.

Harrop and Heath (33), who called attention to the marked resem-blance of the symptoms of " mountain sickness " to those found in casesof polycythemia vera, advanced the opinion that polycythemia vera may bedue to lowered oxygen tension of the arterial blood caused by a changein the alveolar wall, resulting in decreased oxygen diffusion. In threecases of polycythemia they observed a lowering of the arterial oxygensaturation after exercise. The results of these observations would nat-urally suggest that polycythemia should be found more frequently incases of chronic pulmonary diseases, in which pathological alterations inthe lung parenchyma exist producing a decrease in the oxygen saturationof the arterial blood. That such is not commonly the case is a well knownclinical fact; however, actual studies of the blood volume have been re-ported in only a few cases. Plesch (14) and Uhlenbruck (5) found anincrease of the blood volume in a small number of cases with chronicbronchitis and emphysema, but the degree of anoxemia was not deter-mined. Lemon (15), who studied 12 cases of chronic pulmonary emphy-sema, did not find any significant increase in the blood and cell volume,in spite of a low value (average 88 per cent) of the arterial oxygen satura-tion in seven of his cases. From these studies Lemon concluded that thereis no relationship between the development of polycythemia and patho-logical alterations in the alveolar wall. It is clear that the evidence againstthe relationship between development of polycythemia and pulmonarychanges resulting in a decreased oxygen tension is rather negative in char-acter and inconclusive in view of the limited number of cases studied.

A point frequently lost sight of is that the response of the bone marrowto any stimulus calling for the formation of new red cells is extremelyvariable from individual to individual. This fact is easily demonstratedby the response of the blood to low barometric pressures. Although sub-jects are exposed to exactly the same stimulus, some will exhibit a greatincrease in the circulating hemoglobin and red cells, while others will showonly a slight increase. This difference is also found among the residentsat high altitude (Hurtado (34) ). One can not dismiss the hypothesis that

1021


a case of polycythemia vera represents a pathological response of a verysensitive bone marrow to a slight or moderate decrease in the oxygentension of the arterial blood, and that the background of such an occurrenceis the existence of anatomical alterations in the lung parenchyma. In alarge majority of cases such alterations may not be sufficient to cause suchan abnormal response on the part of the hematopoietic system. It is sig-nificant in this connection that in most cases of polycythemia vera in whichthe arterial blood has been studied, the oxygen saturation was foundto be lower than normal.

That we found a hydremic plethora in three cases of pulmonary fibrosisis quite significant and indicates that perhaps these two conditions will befound to be more frequently associated if a greater number of cases arestudied. It is also significant that in these three cases the arterial oxygensaturation was markedly decreased. It is fair to assume from the historythat in these cases the fibrosis of the lung resulting from inhalation ofsilica probably preceded the development of the polycythemia. In two ofthese cases the signs and symptoms with the exception of an enlargedspleen were identical with those of so-called " primary " polycythemia orpolycythemia vera. These results indicate that, whereas in most cases ofchronic pulmonary diseases there is no significant change in the volume ofthe blood except possibly slight concentration even though anoxemia exists,there are, however, occasional cases in which a hydremic plethora developsclosely simulating polycythemia vera. It is interesting that this changewas found only in cases with pulmonary fibrosis. Our cases with emphy-sema, as well as those reported by Lemon (15), in spite of the existenceof anoxemia showed normal blood findings. This cannot be explainedin the light of our present knowledge. Whether or not the nature of thepathological changes in the lungs has some relation to the development ofpolycythemia is unknown.

SUMMARYANDCONCLUSIONSDeterminations of blood and plasma volumes were made on 25 normal

male subjects whose average age was 26 years. Intravenous injection ofbrilliant vital red was used in the estimation of the plasma volume. Stud-ies were made also in 16 cases of pulmonary emphysema and in 14 casesof pulmonary fibrosis. The determinations were made in conjunction withclinical observations and measurements of the pulmonary capacity and ofthe gas content of the arterial blood. From the results of this investiga-tion the following conclusions are drawn:

1. In a group of normal males there were marked variations in thevalues for the total blood volume and its components. There was a highand significant correlation between the volume of the blood and body weightand on this basis the expected values for the blood volume in the patho-logical cases were calculated.

1022


2. In a group of cases with varying degrees of pulmonary emphysema,no significant alterations from the normal were found in the plasma, bloodand cell volume or in the total circulating hemoglobin per kilogram of bodyweight.

3. The mean values for the cell volume and total hemoglobin weredefinitely increased in the group of cases with pulmonary fibrosis. Thiswas due to marked alterations found in three cases, and not to a consistentincrease in all the subjects. The volume of the plasma was normal.

4. No definite correlation was found between the severity and dura-tion of symptoms and the increase in the blood volume.

5. A decreased arterial oxygen saturation was found in the three caseswhich showed marked alterations in the blood volume, but in the remainingcases no correlation was demonstrated between the degree of anoxemia andthe blood findings.

6. Likewise no definite relationship was found between alterations inthe blood volume and changes in the pulmonary capacity.

7. The mean values for the grams of hemoglobin and the red cellvolume per 100 cc. of blood were within normal limits in the group ofcases with pulmonary emphysema, but there was a moderate increase inthose with pulmonary fibrosis. Marked individual variations were ob-served.

8. The mean value for the red cell count was found to be within normallimits in both groups of cases, those with pulmonary emphysema and thosewith fibrosis. No significant changes were demonstrated in the volume orhemoglobin content of the red blood cells.

BIBLIOGRAPHY1. Mendershausen, A., Blutmengenbestimmungen mit der Kongorotmethode.

Ztschr. f. klin. Med., 1923, 97, 468.2. Seyderhelm, R., and Lampe, W., Zur Frage der Blutmengenbestimmung.

III. Colorimetrische Blutmengenbestimmung mit Trypanrot. Ztschr. f.d. ges. exper. Med., 1923, 35, 177.

3. Rusznyak, S., Untersuchungen Zur Frage des Gesamtblutmenge des Men-schen unter normalen und pathologischen Verhaltnissen. DeutschesArch. f. klin. Med., 1927, 157, 186.

4. Rowntree, L. G., and Brown, G. E., The volume of the blood and plasmain health and disease. W. B. Saunders Co., Philadelphia, 1929.

5. UThlenbruck, P., and Vogels, Zum Problem der Zirkulierenden Plasmamenge(Blutmenge) bei Kreislaufstorungen. Ztschr. f. klin. Med., 1931, 118,172.

6. Sparks, M. I., and Haden, R. L., The blood volume in chronic arthritis.Am. J. M. Sc., 1932, 184, 753.

7. Keith, N. M., Rowntree, L. G., and Geraghty, J. T., A method for the deter-mination of plasma and blood volume. Arch. Int. Med., 1915, 16, 547.

8. Fleischer-Hanson, C. C., Determinations of the blood volume in human be-ings. IV. Results with the vital red method. Skandinav. Arch. f. Phys-iol., 1930, 59, 257.

1023


9. Hooper, C. W., Smith, H. P., Belt, A. E., and Whipple, G. H. Blood volumestudies. I. Experimental control of a dye blood volume method. Am. J.Physiol., 1920, 51, 205.

10. Van Slyke, D. D., Gasometric determination of the oxygen and hemoglobinof the blood. J. Biol. Chem., 1918, 33, 127.

11. Hurtado, A., and Boller, C., Studies of total pulmonary capacity and itssubdivisions. I. Normal, absolute and relative values. J. Clin. Invest.,1933, 12, 793.

12. Hurtado, A., and Fray, W. W., Studies of total pulmonary capacity and itssubdivisions. II. Correlation with physical and radiological measure-ments. J. Clin. Invest., 1933, 12, 807.

13. Wintrobe, M. M., Blood of normal men and women. Erythrocyte counts,hemoglobin and volume of packed red cells of 229 individuals. Bull.Johns Hopkins Hosp., 1933, 53, 118.

14. Plesch, J., Untersuchungen uiber die Physiologie und Pathologie der Blut-menge. Ztschr. f. klin. Med., 1922, 93, 241.

15. Lemon, W. S., A study of the effect of chronic pulmonary diseases on thevolume and composition of the blood. Ann. Int. Med., 1929, 3, 430.

16. Price-Jones, C., The size of red blood cells in emphysema. J. Path. andBact., 1921, 24, 326.

17. Osgood, E. E., Hemoglobin, color index, saturation index and volume indexstandards. Redeterminations based on the findings in 137 healthy youngmen. Arch. Int. Med., 1926, 37, 685.

18. Wintrobe, M. M., and Miller, M. W., Normal blood determinations in theSouth. Arch. Int. Med., 1929, 43, 96.

19. Foster, P. C., and Johnson, J. R., Oxygen capacity and hemoglobin contentof normal blood of men. Proc. Soc. Exper. Biol. and Med., 1931, 28,929.

20. Bert, Paul, Sur la richesse en hemoglobine du sang des animaux vivant surles hauts lieux. Comptes rend. Acad. d. sc., Par., 1882, 94, 805.

21. Viault, F., Sur l'augumentation considerable du nombre des globules rougesdans le sang chez les habitants des hauts plateaux de l'Amerique du Sud.Comptes rend. Acad. d. sc., Par., 1890, 111, 917.

22. Miescher, F., Ueber die Beziehungen zwischen Meereshoehe und Beschaff-enheit des Blutes. Cor. Blatt. f. Schweitz. Artze, 1893, 23, 809.

23. Bence, J., Drei Falle von Polyglobulie mit Milztumor. Deutsche med.Wchnschr., 1906, 32, 1451.

24. Dersca, A., and Valter, V., Les modifications sanguines a la Suite del'oxygenotherapie Intraveineuse. Paris Med., 1929, 2, 314.

25. Barcroft, J., and Stephens, J. G., Observations upon the size of the spleen.J. Physiol., 1927, 64, 1.

26. McNee, J. W., The spleen: its structure, functions and diseases. Lancet,1931, 1, 1009.

27. Douglas, C. G., The determination of the total oxygen capacity and bloodvolume at different altitudes by the carbon monoxide method. J. Phys-iol., 1910, 40, 472.

28. Douglas, C. G., and Haldane, J. S., Henderson, Y., Schneider, E. C., Physi-ological observations made on Pike's Peak, Colorado, with special refer-ence to adaptation to low barometric pressures. Phil. Tr. Roy. Soc.,1913, 203, 185.

29. Smith, H. P., Belt, A. E., Arnold, H. R., and Carrier, E. B., Blood volumechanges at high altitude. Am. J. Physiol., 1925, 71, 395.

1024


30. Lippmann, A., Blutzusammensetzung und Gesamtblutmenge bei Hochge-birgsbewohnern. Klin. Wchnschr., 1926, 5, 1406.

31. Laquer, F., Untersuchungen der Gesamtblutmenge im Hochgebirge mit derGriesbachschen Kongorotmethode. Klin. Wchnschr., 1924, 3, 7.

32. Monge, C., Les Rrythremies de l'Altitude. Masson et Cie, Paris, 1929.33. Harrop, G. A., and Heath, E. H., Pulmonary gas diffusion in polycythemia

vera. J. Clin. Invest., 1927, 4, 53.34. Hurtado, A., Studies at high altitude. Blood observations on the Indian

natives of the Peruvian Andes. Am. J. Physiol., 1932, 100, 487.

studydm5migu4zj3pb.cloudfront.net/manuscripts/100000/... · study of the blood in chronic...

Documents